Ketals of delta3-a-norandrostene-17beta-ol-2-one and delta3-a-norpregnene-2, 20-dione and their 3, 5-dihydroxy derivatives



United States Patent 6 Claims. (Cl. 260-6403) ABSCT OF THE DISCLOSURE This invention relates to the Z-ketal derivatives of A A-norandrostene-17fl-ol-2-one and A-norandrostane 3,9, 5 9,17fi-triol-2-one and the 2,20-bis-ketals of A -A-norpregnene-2,20-dione and A-norpregnane-3fi,5 8-diol-2,20= dione. These compounds are useful as intermediates in preparing A -A-norandrostene-2-one-3,17,8-diol and A -A- norpregnene-2,20-dione-3-ol, by treating the 3,5-dihydroxy derivatives with an acid to yield the free keto derivative and then with a dilute base to dehydrate the compound formed to yield the A -3-hydroxy final product.

This application is a division of our application, Ser. No. 359,417, filed Apr. 13, 1964, now Patent No. 3,324,171.

This invention relates to the synthesis of steroids and has for its object the provision of a new class of physiologically active steroids, which may be represented by the formula wherein R is S-acetyl, fi-R'O or keto, and R is hydrogen, the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, or an alkyl of less than twelve carbon atoms.

Those compounds of the above formula, wherein R is B-R'O or keto, are physiologically active substances which possess both androgenic and anabolic activities. Hence, these compounds can be used in lieu of known androgenic or anabolic steroids, such as testosterone, in the treatment of conditions which respond to such treatment, being formulated for such administration in the same type of parenteral preparations as testosterone, for example, with concentration and/or dosage based on the activity of the particular compound.

Those compounds of the above formula, wherein R is fl-acetyl, are physiologically active substances which possess antiandrogenic activity. Hence, these compounds can be used in lieu of known antiandrogenic steroids, such as A-norprogesterone, in the treatment of hyperandrogenic acne, being formulated for such administration in topical preparations with concentration and/or dosage based on the activity of the particular compound.

The new compounds of this invention are prepared by either of two alternative methods. In the first method, A- nortestosterone or A-norprogesterone is converted to its Z-ketal or 2,20-diketal derivative, respectively, by reacting with a 1,2- or 1,3-dihydric alcohol, such as ethylene glycol and propylene glycol, in the presence of an acid catalyst, such as p-toluenesulfonic acid and perchloric acid. The reaction is preferably conducted in the presence of an organic solvent, such as benzene, for the steroid reactant, at an elevated temperature, such as the reflux temperature of the solvent.

This first step of the process of this invention yields new intermediates of this invention of the formula wherein R" is the ketal of fi-acetyl with the diyhdric alcohol or fi-hydroxy, and A is lower alkylene, preferably ethylene or l',2.-propylene.

The ketals are then reacted with osmium tetroxide in the presence of a base, such as an organic base (e.g., pyridine). The reaction is preferably carried out in the presence of an organic solvent for ,the steroid reactant, such as benzene, at any normal temperature, such 'as ambient temperature.

This second step of the process yields new intermediates of this invention of the formula wherein R" and A are as hereinbefore defined.

The 3,8,5fl-dihydroxy intermediates are then hydrolyzed in the usual manner, as by treatment with a dilute'aqueous acid, such as p-toluenesulfonic acid and sulfuric'acid, preferably in the presence'of an organic solvent for" the steroid reactant at an elevated temperature, such as the reflux temperature of the solvent.

This third step of the process yields new intermediates of this invention of the formula The following examples are illustrative of the invention (all temperatures being in Centigrade):

Example 1.-A -A-norandrostene-l7fl-ol-2-one 2-ethylene ketal A mixture of 4 g. of A-nortestosterone and 65 mg. of ptoluenesulfonic acid is stirred and refluxed in 250 m1. of benzene and 40 m1. of ethylene glycol for seven days and the water removed by a calcium carbide trap. The benzene layer is separated, and the ethylene glycol layer is diluted with water and extracted with additional benzene. The combined benzene extracts are washed in 8% salt solution, dried over sodium sulfate and evaporated to dryness. The residue is crystallized from isopropyl ether and gives about 2.45 g. of A A norandrostene- 175 01 2 one 2 ethylene ketal, M.P. about 149.5- 150.5; [1x1 4298 (ethanol);

h 2.88, 6.03, 8.83, 907, 9.26, and 9.53

7 9.22 (s, 18-Me), 8.96 (s, 19-Me), 6.32 (In, 17-H), 6.05 (s, ketal methylenes) and 4.73 (d, J: 1 cps, 3-H).

Analysis.-Calcd. for C H O (318.44): C, 75.43; H, 9.50. Found: C, 75.52; H, 9.47.

Example 2.A -A-norpregnene-2,20-dione 2,20- bis-ethylene ketal Example 3.A-norandrostane-2-one-3,6,513,17B- triol 2-ethylene ketal A mixture of 50 mg. of A A norandrostene 17,8- ol-2-one Z-ethylene ketal and 47 mg. of osmium tetroxide in 0.4 ml. of pyridine and 10 ml. of benzene is stirred at room temperature for 89 hours. The reaction mixture is evaporated to dryness and the residue dissolved in 8 ml. of chloroform and stirred with 16 m1. of a 1% potassium hydroxide solution containing 1.6 g. of mannitol for 3 hours. The chloroform layer is separated and dried over sodium sulfate. Evaporation gives about 54 mg. of A- norandrostane 2 one 35,56,175 triol 2-ethylene ketal having a melting point of 204207. The analytical sampie is prepared by recrystallization from benzene, M.P. about 208-209, [a] +46 (ethanol);

'y 9.25 (s, 18-Me), 9.01 (s, 19-Me), 6.37 (m, 17-

H) and 6.04 (s, ketal methylenes).

Analysis.Calcd. for 1-1 0 9.15. Found: C, 68.19; H, 9.13.

Example 4.-A-nonpregnane-2,20-dione-3 18,5;3-diol 2,20-bis-ethylene ketal Following the procedure in Example 3 but substituting A -A-norpregnene-2,20-dione 2,20-bis-ethylene ketal for A A norandrostene 175 ol 2 one Z-ethylene ketal there is obtained A-norpregnane-2,20dione-313,5,8-diol 2,20-bis-ethylene ketal.

Example 5.-A-norandrostane-2-one-3;8,5;9,17 3-triol from ethyl acetate gives about 56 mg. of A-norandrostane- 2-one-3;8,5B,17fi-triol having a melting point of about 202204. Recrystallization from ethyl acetate gives the analytical sample having M.P. about 206207; [a] -4O (EtOH);

)tfifi 2.86, 2.93, and 5.75;:

2 9.20 (s, 18-Me), 8.85 (s, 19-Me), 6.35 (m, 17- H), and 5.55 (s, 3-H).

Analysis.Calcd. for C H O (308.42): C, 70.10; H, 9.15. Found: C, 70.20; H, 9.11.

Example 6.A-norpregnane-2,20-dione-3fi,5B-diol Example 7.A -norandrostene-2-one-3,17fi3-diol (1) A mixture of 1.18 g. of A-nortestosterone and 1 g. of osmium tetroxide in 1 ml. of pyridine and 20 ml. of benzene is stirred at room temperature for 65 /2 hours. The reaction mixture is evaporated to dryness and the residue is dissolved in ml. of chloroform and stirred with 200 ml. of a 1% potassium hydroxide solution containing 20 g. of mannitol for 2 /2 hours. The layers are separated and the aqueous phase is acidified with hydrochloric acid and extracted five times with chloroform. The chloroform extracts are dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane gives about 292 mg. of A -A-norandrostene-Z-one- 17B-diol having a melting point of 2545-2555". Recrystallization from acetone-hexane gives the analytical sample having M.P. about 259-260"; [u] :+43 (EtOH); hfif; 2.93, 3.18, 5.87, and 602p; hEEfif 265m (e= 12,700) y X; 9.19 (s, 18-Me), 8.83 (s, 19-Me), 6.33 (m, 17- H), 4.63 (s, 3-OH).

Analysis.Calcd. for C H O (290.39): C, 74.44; H, 9.03. Found: C, 74.31; H, 9.01.

(2) A solution of 24 mg. of A-norandrostane-Z-one- 3a,5ot,l7}3-tfl0l in 5 ml. of chloroform is stirred with 10 ml. of a 1% potassium hydroxide solution containing 1 g. of mannitol for 3 hours. The workup procedure described in Example 7, part 1, is employed and gives A A-norandrostene-2-one-3,17fl-diol.

Example 8.-A -A-norpregnene-2,20-dione-3-ol Following the procedures of Example 7, but substituting A-norprogesterone for A-nortestosterone in part 1 or A- norpregnane-2,20-dione-304,5a-di0l for A-norandrostane- 2-one 3u,5a,17;3-triol in part 2, there is obtained A -A-norpregnene-2,20-dione-3-ol.

What is claimed is:

1. A compound of the formula wherein R" is selected from the group consisting of the ketal of fl-actyl with a lower alkanediol and fi-hydroxy, and A is lower alkylene.

6 2. The compound of claim 1 having the name A -A- wherein R" is selected from the group consisting of the norandrostene-l7fi-o1-2-one 2-ethylene ketal. ketal of fi-acetyl with a lower alkanediol and fi-hydroxy,

3. The compound of claim 1 having the name A -A-norand A is lower alkylene.

pregnene-2,20-dione 2,20-bis-ethylene ketal. 5. The compound of claim 4 having the name A-noran- 4. A compound of the formula 5 drostane-2-one-3B,5fi,17/3-t1iol Z-ethylene ketal.

6. The compound of claim 4 having the name A-norl\ pregnane-2,20-dione-3fl,5fl-dio1, 2,20-bis-ethylene ketal. J References Cited 10 UNITED STATES PATENTS 3,346,617 10/1967 Levine et a1. 260340.9 X

ALEX MAZEL, Primary Examiner.

15 I. H. TURNIPSEED, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,377 ,360 April 9 1968 Seymour D. Levine et a1 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 20, "diyhdric" should read dihydric lines 32 to 42, the formula should appear as shown below:

lines 55 to 64, the formula should appear as shown below:

Column 3 line 53 "Y" should read T mn 4 line 19 "A norandroscene' should read A A-Norandrostene line 33, "l7B-dio1" should read 3,17B-diol line 37, "ySi(CH3) should read TSi (CH 4 line 43 "3oz 5a should read 3B, 5B, line 74, "B-actyl" should read B-acetyl Column 5, lines 6 to 15, the formula should appear as shown below:

O HO Signed and sealed this 23rd day of September 1969.

(SEAL) Atflest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

